Abstract
Craniofacial morphogenesis is highly complex, as is the anatomical region involved. Errors during this process, resulting in orofacial clefts, occur in more than 400 genetic syndromes. Some cases of cleft lip and/or palate (CLP) are caused by mutations in single genes; however, complex interactions between genetic and environmental factors are considered to be responsible for the majority of non-syndromic CLP development. The aim of the current study was to identify genetic risk factors in patients with isolated cleft palate (CP) by whole genome sequencing. Patients with isolated CP (n = 30) recruited from the Riga Cleft Lip and Palate Centre, Institute of Stomatology, Riga, were analyzed by whole genome sequencing. Pathogenic or likely pathogenic variants were discovered in genes associated with CP (TBX22, COL2A1, FBN1, PCGF2, and KMT2D) in five patients; hence, rare disease variants were identified in 17% of patients with non-syndromic isolated CP. Our results were relevant to routine genetic counselling practice and genetic testing recommendations. Based on our data, we propose that all newborns with orofacial clefts should be offered genetic testing, at least for a panel of known CLP genes. Only if the results are negative and there is no suggestive family history or additional clinical symptoms (which would support additional exome or genome-wide investigation), should multifactorial empiric recurrence risk prediction tools be applied for families.
Highlights
Craniofacial morphogenesis is a highly complex process, reflecting the sophistication of the anatomical region it concerns
A total of 30 patients with isolated cleft palate (CP) were analyzed by whole genome sequencing (WGS), and pathogenic or likely pathogenic variants were discovered in genes associated with CP (TBX22, COL2A1, FBN1, PCGF2, KMT2D) in five of these patients, as detailed below
TBX22 has been described in several previous studies (Braybrook et al, 2001; Marçano et al, 2004; Demeer et al, 2018) as a cause of X-linked semi-dominant CP and ankyloglossia (CPX) (OMIM)
Summary
Craniofacial morphogenesis is a highly complex process, reflecting the sophistication of the anatomical region it concerns Impairment of this process, resulting in orofacial clefts, occurs in more than 400 genetic syndromes, with various modes of inheritance (OMIM, 2020). Mechanisms leading to the development of isolated cleft palate (CP) are thought to differ from those leading to CLP, as a median defect; this classification was proposed in 1971 and remains valid to date (Fogh-Andersen, 1971). CLP prevalence is 3.4–22.9 per 10,000 births and it is higher in South America and Asia, emphasizing the difference in population genetics. By far the most common genetic syndrome associated with orofacial cleft is van der Woude syndrome type 1 and 2, caused by pathogenic variants in IRF6 and GRHL3 genes, . Van der Woude syndrome, is a rare exception, as both forms CLP and CP can be present in this syndrome, along with the lip pits (Online Mendelian Inheritance in Man, 1960)
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